The natural history, prognosis,management and molecular basis of gastrinomas and other malignant pancreatic endocrine tumors (PET's) in patients without (sporadic disease) or with multiple endocrine neoplasia-type 1 (MEN1) is largely based on antedotal reports and small series. Gastrinomas are the most common symptomatic, malignant PET in patients with or without MEN1 and sufficient numbers of these patients have been entered into our protocols to allow systematic assessment. Studies are now underway, evaluating the natural history of these tumors including the presentation and initial diagnosis and definition of factors determining prognosis including attempting to identify molecular characteristics of the tumor that have prognostic significance. Our studies have identified a cohort of 25% of patients in whom the gastrinomas have aggressive growth and 25% who have multiple endocrine neoplasia type 1 (MEN1). Our longterm studies this year demonstrate patients with ZES/MEN1 develope meningiomas as an intrinsic MEN1 tumor and have an increased occurrence of severe esophageal disease including the premalignant condition, dysplasia. The identification of patients with different prognoses allows us to do molecular studies of the tumor to attempt to identify genetic abnormalities that might contribute to aggressive growth. An increased expression of the insulin-like growth factor 1 (IGF-1) and its receptor was found in gastrinomas this year and their presence correlated with a low curability, increased tumor growth nd the development of metastases. In previous studies we identified abnormalities in the MEN1 gene, HER2/neu gene, p16 gene and other growth factors but none correlated as strongly as IGF-1/IGF-1R alterations with aggressive tumor growth. The availability of these molecular prognostic markers may prove clinically useful to identify patients who need more aggressvie anti-tumor treatment. Our longterm surgical studies demonstrated for the first time this year that routine surgical exploration for cure increases patient survival and therefore should be done in all patients.